This invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.
The following publications, patents and patent applications are cited in this application as superscript numbers:
1Hemler and Takada, European Patent Application Publication No. 330,506, published Aug. 30, 1989
2Elices, et al., Cell, 60:577-584 (1990)
3Springer, Nature, 346:425-434 (1990)
4Osborn, Cell, 62:3-6 (1990)
5Vedder, et al., Surgery, 106:509 (1989)
6Pretolani, et al., J. Exp. Med., 180:795 (1994)
7Abraham, et al., J. Clin. Invest., 93:776 (1994)
8Mulligan, et al., J. Immunology, 150:2407 (1993)
9Cybulsky, et al., Science, 251:788 (1991)
10Li, et al., Arterioscler. Thromb., 13:197 (1993)
11Sasseville, et al., Am. J. Path., 144:27 (1994)
12Yang, et al., Proc. Nat. Acad. Science (USA), 90:10494 (1993)
13Burkly, et al., Diabetes, 43:529 (1994)
14Baron, et al., J. Clin. Invest., 93:1700 (1994)
15Hamann, et al., J. Immunology, 152:3283 (1994)
16Yednock, et al., Nature, 356:63 (1992)
17Baron, et al., J. Exp. Med., 177:57 (1993)
18van Dinther-Janssen, et al., J. Immunology, 147:4207 (1991)
19van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52:672 (1993)
20Elices, et al., J. Clin. Invest., 93:405 (1994)
21Postigo, et al., J. Clin. Invest., 89:1445 (1991)
22Paul, et al., Transpl. Proceed., 25:813 (1993)
23Okarhara, et al., Can. Res., 54:3233 (1994)
24Paavonen, et al., Int. J. Can., 58:298 (1994)
25Schadendorf, et al., J. Path., 170:429 (1993)
26Bao, et al., Diff., 52:239 (1993)
27Lauri, et al., British J. Cancer, 68:862 (1993)
28Kawaguchi, et al., Japanese J. Cancer Res., 83:1304 (1992)
29Kogan, et al., U.S. Pat. No. 5,510,332, issued Apr. 23, 1996
30International Patent Appl. Publication No. WO 96/01644
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
VLA-4 (also referred to as xcex14xcex21 integrin and CD49d/CD29), first identified by Hemler and Takada1 is a member of the xcex21 integrin family of cell surface receptors, each of which comprises two subunits, an xcex1 chain and a xcex2 chain. VLA-4 contains an xcex14 chain and a xcex21 chain. There are at least nine xcex21 integrins, all sharing the same xcex21 chain and each having a distinct a chain. These nine receptors all bind a different complement of the various cell matrix molecules, such as fibronectin, laminin, and collagen. VLA-4, for example, binds to fibronectin. VLA-4 also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on cytokine-activated human umbilical vein endothelial cells in culture. Distinct epitopes of VLA-4 are responsible for the fibronectin and VCAM-1 binding activities and each activity has been shown to be inhibited independently.2 
Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive for leukocytes. The mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection. For reviews of adhesion receptors of the immune system, see, for example, Springer3 and Osborn4.
Inflammatory brain disorders, such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium/leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue. Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases. The leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis.
In other organ systems, tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes. For example, it has been shown that the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to the injured tissue causing still further insult (Vedder et al.5). Other inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma6-8, Alzheimer""s disease, atherosclerosis9-10, AIDS dementia11, diabetes12-14 (including acute juvenile onset diabetes), inflammatory bowel disease15 (including ulcerative colitis and Crohn""s disease), multiple sclerosis16-17, rheumatoid arthritis18-21, tissue transplantation22, tumor metastasis23-28, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
In view of the above, assays for determining the VLA-4 level in a biological sample containing VLA-4 would be useful, for example, to diagnosis VLA-4 mediated conditions. Additionally, despite these advances in the understanding of leukocyte adhesion, the art has only recently addressed the use of inhibitors of adhesion in the treatment of inflammatory brain diseases and other inflammatory conditions29,30. The present invention addresses these and other needs.
This invention provides compounds which bind to VLA-4. Such compounds can be used, for example, to assay for the presence of VLA-4 in a sample and in pharmaceutical compositions to inhibit cellular adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4. The compounds of this invention have a binding affinity to VLA-4 as expressed by an IC50 of about 15 xcexcM or less (as measured using the procedures described in Example A below) which compounds are defined by formula Ia and Ib below: 
wherein,
in formula Ia, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a fused ring heteroaryl or a fused ring heterocyclic group optionally containing 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
in formula Ib, R1 and R2, together with the carbon atom and Wxe2x80x2 to which they are bound respectively, are joined to form a fused ring heterocyclic group optionally containing 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
and further wherein said fused ring heteroaryl or fused ring heterocyclic group of formula Ia or Ib is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)2xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl;
R3 is selected from the group consisting of:
(a) xe2x80x94(CH2)xxe2x80x94Arxe2x80x94R35 where R35 is selected from the group consisting of xe2x80x94Oxe2x80x94Zxe2x80x94NR36R36xe2x80x2 and xe2x80x94Oxe2x80x94Zxe2x80x94R37 wherein R36 and R36xe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R36 and R36xe2x80x20 are joined to form a heterocycle or a substituted heterocycle, R37 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of xe2x80x94C(O)xe2x80x94 and xe2x80x94SO2xe2x80x94,
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
x is an integer of from 1 to 4; and
(b) Ar1xe2x80x94Ar2xe2x80x94C1-10alkyl-, Ar1xe2x80x94Ar2xe2x80x94C2-10alkenyl- and Ar1xe2x80x94Ar2xe2x80x94C2-10alkynyl-, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rb; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra;
R3xe2x80x2 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, aryl C1-10alkyl, heteroaryl, and heteroaryl C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb;
Q is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2, and xe2x80x94NR4xe2x80x94;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R4 and R1 or R4 and R2, together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group;
W is selected from the group consisting of nitrogen and carbon; and
Wxe2x80x2 is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O)2;
X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and xe2x80x94NRxe2x80x3Rxe2x80x3 where each Rxe2x80x3 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
Ra is selected from the group consisting of Cy, xe2x80x94ORd, xe2x80x94NO2, halogen xe2x80x94S(O)mRd, xe2x80x94SRd, xe2x80x94S(O)2ORd, xe2x80x94S(O)mNRdRe, xe2x80x94NRdRe, xe2x80x94O(CRfRg)nNRdRe, xe2x80x94C(O)Rd, xe2x80x94CO2Rd, xe2x80x94CO2(CRfRg)nCONRdRe, xe2x80x94OC(O)Rd, xe2x80x94CN, xe2x80x94C(O)NRdRe, xe2x80x94NRdC(O)Re, xe2x80x94OC(O)NRdRe, xe2x80x94NRdC(O)ORe, xe2x80x94NRdC(O)NRdRe, xe2x80x94CRd(Nxe2x80x94ORe), CF3, and xe2x80x94OCF3; wherein Cy is optionally substituted with one to four substituents independently selected from Rc;
Rb is selected from the group consisting of Ra, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10 alkyl, heteroaryl, C1-10 alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc;
Rc is selected from the group consisting of halogen, amino, carboxy, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4alkyl, hydroxy, CF3, and aryloxy;
Rd and Re are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cyxe2x80x94C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc; or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rf and Rg are independently selected from hydrogen, C1-10 alkyl, Cy and Cyxe2x80x94C1-10 alkyl; or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
m is an integer from 1 to 2;
n is an integer from 1 to 10;
and pharmaceutically acceptable salts thereof.
Preferred compounds of this invention are represented by formula II below: 
wherein
R3, R3xe2x80x2, Q and X are as defined above;
ring A forms a heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic ring;
ring B forms an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring;
and pharmaceutically acceptable salts thereof.
More preferred compounds of this invention are represented by formula IIIa below: 
wherein
R3, R3xe2x80x2 and X are as defined above;
Y is oxygen, sulfur, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94,  greater than NR5 or  greater than Nxe2x80x94S(O)2R6;
R4xe2x80x2 is selected from the group consisting of hydrogen and alkyl;
R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)2xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl;
Wxe2x80x3 is selected from the group consisting of nitrogen and carbon (i.e., CH);
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of this invention are represented by formula IIIb below: 
wherein R4, R7, R8, Wxe2x80x3, X and Y are as defined above; R9 is selected from the group consisting of xe2x80x94Oxe2x80x94Zxe2x80x94NR11R11xe2x80x2 and xe2x80x94Oxe2x80x94Zxe2x80x94R12 wherein R11 and R11xe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, and where R11 and R11xe2x80x2 are joined to form a heterocycle or a substituted heterocycle, R12 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of xe2x80x94C(O)xe2x80x94 and xe2x80x94SO2xe2x80x94,
x is an integer of from 1 to 4;
and pharmaceutically acceptable salts thereof.
Other preferred compounds of this invention include those having formula IIIc: 
wherein
R3, R3xe2x80x2, R4xe2x80x2, R7, R8 and X are as defined herein; and
R10 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)2xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl;
and pharmaceutically acceptable salts thereof.
Still other preferred compounds of this invention are represented by formula IVa and IVb below: 
wherein,
in formula IVa, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a fused ring heteroaryl or fused ring heterocyclic group optionally containing 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
in formula IVb, R1 and R2, together with the carbon atom and Wxe2x80x2 to which they are bound respectively, are joined to form a fused ring heterocyclic group optionally containing 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
and further wherein said fused ring heteroaryl or fused ring heterocyclic group of formula IVa or IVb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)2xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl;
R13 is selected from the group consisting of hydrogen, C1-10 alkyl, Cy, and Cyxe2x80x94C1-10 alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from Ra; and Cy is optionally substituted with one to four substituents independently selected from Rb;
R14 is selected from the group consisting of:
(a) xe2x80x94(CH2)xxe2x80x94Arxe2x80x94R35 where R35 is selected from the group consisting of xe2x80x94Oxe2x80x94Zxe2x80x94NR36R36xe2x80x2 and xe2x80x94Oxe2x80x94Zxe2x80x94R37 wherein R36 and R36xe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R36 and R36xe2x80x2 are joined to form a heterocycle or a substituted heterocycle, R37 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of xe2x80x94C(O)xe2x80x94 and xe2x80x94SO2xe2x80x94,
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
x is an integer of from 1 to 4; and
(b) Ar1xe2x80x94Ar2xe2x80x94C1-10alkyl-, Ar1xe2x80x94Ar2xe2x80x94C2-10alkenyl- and Ar1xe2x80x94Ar2xe2x80x94C2-10alkynyl-, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rb; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra;
R15 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, aryl C1-10alkyl, heteroaryl, and heteroaryl C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb;
Ra is selected from the group consisting of Cy, xe2x80x94ORd, xe2x80x94NO2, halogen xe2x80x94S(O)mRd, xe2x80x94SRd, xe2x80x94S(O)2ORd, xe2x80x94S(O)mNRdRe, xe2x80x94NRdRe, xe2x80x94O(CRfRg)nNRdRe, xe2x80x94C(O)Rd, xe2x80x94CO2Rd, xe2x80x94CO2(CRfRg)nCONRdRe, xe2x80x94OC(O)Rd, xe2x80x94CN, xe2x80x94C(O)NRdRe, xe2x80x94NRdC(O)Re, xe2x80x94OC(O)NRdRe, xe2x80x94NRdC(O)ORe, xe2x80x94NRdC(O)NRdRe, xe2x80x94CRd(Nxe2x80x94ORe), CF3, and xe2x80x94OCF3; wherein Cy is optionally substituted with one to four substituents independently selected from Rc;
Rb is selected from the group consisting of Ra, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10 alkyl, heteroaryl, C1-10alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc;
Rc is selected from the group consisting of halogen, amino, carboxy, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4 alkyl, hydroxy, CF3, and aryloxy;
Rd and Re are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cyxe2x80x94C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc; or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rf and Rg are independently selected from hydrogen, C1-10 alkyl, Cy and Cyxe2x80x94C1-10 alkyl; or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rh is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl or xe2x80x94SO2Ri; wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substitutents independently selected from Ra; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb;
Ri is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rc;
Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
m is an integer from 1 to 2;
n is an integer from 1 to 10;
W is selected from the group consisting of carbon and nitrogen;
Wxe2x80x2 is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O)2;
Xxe2x80x2 is selected from the group consisting of xe2x80x94C(O)ORd, xe2x80x94P(O)(ORd)(ORe), xe2x80x94P(O)(Rd)(ORe), xe2x80x94S(O)mORd, xe2x80x94C(O)NRdRh, and -5-tetrazolyl;
and pharmaceutically acceptable salts thereof.
Other preferred compounds of this invention are represented by formula Va: 
wherein
Wxe2x80x3, Y, R7, R8, R13, R14, R15 and Xxe2x80x2 are as defined above;
and pharmaceutically acceptable salts thereof.
Other preferred compounds are those of formula Vb: 
wherein
R7, R8, R10, R13, R14, R15 and Xxe2x80x2 are as defined herein;
and pharmaceutically acceptable salts thereof.
Still other preferred compounds include those represented by formula VIa and VIb: 
wherein,
in formula VIa, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a fused ring heteroaryl or fused ring heterocyclic group optionally containing 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
in formula VIb, R1 and R2, together with the carbon atom and Wxe2x80x2 to which they are bound respectively, are joined to form a fused ring heterocyclic group optionally containing 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
and further wherein said fused ring heteroaryl or fused ring heterocyclic group of formula VIa or VIb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)2xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl;
R23 is selected from the group consisting of hydrogen, C1-10 alkyl optionally substituted with one to four substituents independently selected from Raxe2x80x2 and Cy optionally substituted with one to four substituents independently selected from Rbxe2x80x2;
R24 is selected from the group consisting of Ar1xe2x80x94Ar2xe2x80x94C1-10 alkyl, Ar1xe2x80x94Ar2xe2x80x94C2-10 alkenyl, Ar1xe2x80x94Ar2xe2x80x94C2-10 alkynyl, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rbxe2x80x2; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Raxe2x80x2;
R25 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, aryl C1-10alkyl, heteroaryl, and heteroaryl C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Raxe2x80x2, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rbxe2x80x2;
Raxe2x80x2 is selected from the group consisting of Cy, xe2x80x94ORdxe2x80x2, xe2x80x94NO2, halogen xe2x80x94S(O)mRdxe2x80x2, xe2x80x94SRdxe2x80x2, xe2x80x94S(O)2ORdxe2x80x2, xe2x80x94S(O)mNRdxe2x80x2Rexe2x80x2, xe2x80x94NRdxe2x80x2Rexe2x80x2, xe2x80x94O(CRfxe2x80x2Rgxe2x80x2)nNRdxe2x80x2Rexe2x80x2, xe2x80x94C(O)Rdxe2x80x2, xe2x80x94CO2Rdxe2x80x2, xe2x80x94CO2(CRfxe2x80x2Rgxe2x80x2)nCONRdxe2x80x2Rexe2x80x2, xe2x80x94OC(O)Rdxe2x80x2, xe2x80x94CN, xe2x80x94C(O)NRdxe2x80x2Rexe2x80x2, xe2x80x94NRdxe2x80x2C(O)Rexe2x80x2, xe2x80x94OC(O)NRdxe2x80x2Rexe2x80x2, xe2x80x94NRdxe2x80x2C(O)ORexe2x80x2, xe2x80x94NRdxe2x80x2C(O)NRdxe2x80x2Rcxe2x80x2, xe2x80x94CRdxe2x80x2(Nxe2x80x94ORexe2x80x2), CF3, and xe2x80x94OCF3;
wherein Cy is optionally substituted with one to four substituents independently selected from Rcxe2x80x2;
Rbxe2x80x2 is selected from the group consisting of Raxe2x80x2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10 alkyl, heteroaryl C1-10alkyl,
wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rcxe2x80x2;
Rcxe2x80x2 is selected from the group consisting of halogen, amino, carboxy, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4 alkyl, hydroxy, CF3, and aryloxy;
Rdxe2x80x2 and Rexe2x80x2 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cyxe2x80x94C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rcxe2x80x2; or Rdxe2x80x2 and Rexe2x80x2 together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rfxe2x80x2 and Rgxe2x80x2 are independently selected from hydrogen, C1-10 alkyl, Cy and Cyxe2x80x94C1-10 alkyl; or Rfxe2x80x2 and Rgxe2x80x2 together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rhxe2x80x2 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, or xe2x80x94SO2Rixe2x80x2;
wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substitutents independently selected from Raxe2x80x2; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rbxe2x80x2;
Rixe2x80x2 is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and aryl;
wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rcxe2x80x2;
Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
Xxe2x80x2 is selected from the group consisting of xe2x80x94C(O)ORdxe2x80x2, xe2x80x94P(O)(ORdxe2x80x2)(ORexe2x80x2), xe2x80x94P(O)(Rdxe2x80x2)(ORexe2x80x2), xe2x80x94S(O)mORdxe2x80x2, xe2x80x94C(O)NRdxe2x80x2Rhxe2x80x2, and -5-tetrazolyl;
m is an integer from 1 to 2;
n is an integer from 1 to 10;
and pharmaceutically acceptable salts thereof.
Yet another preferred set of compounds of this invention are those represented by formula VIIa below: 
wherein
R7, R8, R23, R24 R25, Wxe2x80x3, Y are as defined above Xxe2x80x3 is selected from the group consisting of xe2x80x94C(O)ORd, xe2x80x94P(O)(ORd)(ORe), xe2x80x94P(O)(Rd)(ORe), xe2x80x94S(O)mORd, xe2x80x94C(O)NRdRh, and -5-tetrazolyl;
and pharmaceutically acceptable salts thereof.
Other preferred compounds are those of formula VIIb: 
wherein
R7, R8, R10, R23, R24, R25 and Xxe2x80x3 are as defined herein;
and pharmaceutically acceptable salts thereof.
In formula Ia-b, II, IIIa-c above, when X is other than xe2x80x94OH or pharmaceutical salts thereof, X is a substituent which will convert (e.g., hydrolyze, metabolize, etc.) in vivo to a compound where X is xe2x80x94OH or a salt thereof. Accordingly, suitable X groups are any art recognized pharmaceutically acceptable groups which will hydrolyze or otherwise convert in vivo to a hydroxyl group or a salt thereof including, by way of example, esters (X is alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, alkenoxy, substituted alkenoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, and the like).
In the compounds of formula Ia-b, IVa-b, VIa-b above, R1 and R2 are preferably joined to form a benzimidazolyl, benzoxazolyl, benzothiazolyl, substituted benzimidazolyl, substituted benzoxazolyl, substituted benzothiazolyl group, quinazolinyl or substituted quinazolinyl group. In formula IIIa-b, W is preferably nitrogen.
In a preferred embodiment of this invention, R3 is selected from all possible isomers arising by substitution with the following groups:
3-[(CH3)2NC(O)O-]benzyl,
4-[(CH3)2NC(O)O-]benzyl,
4-[(CH3)2NS(O)2O-]benzyl,
4-[(piperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(piperidin-4xe2x80x2-yl)C(O)O-]benzyl,
4-[(1xe2x80x2-methylpiperidin-4xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-hydroxypiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-formyloxypiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-ethoxycarbonylpiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-carboxylpiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(3xe2x80x2-hydroxymethylpiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-hydroxymethylpiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-phenyl-1xe2x80x2-Boc-piperidin-4xe2x80x2-yl)-C(O)O-]benzyl,
4-[(4xe2x80x2-piperidon-1xe2x80x2-yl ethylene ketal)C(O)O-]benzyl,
4-[(piperazin-4xe2x80x2-yl)-C(O)O-]benzyl,
4-[(1xe2x80x2-Boc-piperazin-4xe2x80x2-yl)-C(O)O-]benzyl,
4-[(4xe2x80x2-methylpiperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-methylhomopiperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(2-hydroxyethyl)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-phenylpiperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(pyridin-2-yl)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(4-trifluoromethylpyridin-2-yl)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(pyrimidin-2-yl)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-acetylpiperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(phenylC(O)-)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(pyridin-4-ylC(O)-)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(phenylNHC(O)-)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(phenylNHC(S)-)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-methanesulfonylpiperazin-1xe2x80x2-yl-C(O)O-)benzyl,
4-[(4xe2x80x2-trifluoromethanesulfonylpiperazin-1xe2x80x2-yl-C(O)O-)benzyl,
4-[(morpholin-4xe2x80x2-yl)C(O)O-]benzyl,
3-nitro-4-[(morpholin-4xe2x80x2-yl)-C(O)O-]benzyl,
4-[(thiomorpholin-4xe2x80x2-yl]C(O)O-]benzyl,
4-[(thiomorpholin-4xe2x80x2-yl sulfone)-C(O)O-]benzyl, (alternative nomenclature 4-[(1,1-dioxothiomorpholin-4-yl)-C(O)O-]benzyl),
4-[(pyrrolidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(2xe2x80x2-methylpyrrolidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(2xe2x80x2-(methoxycarbonyl)pyrrolidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(2xe2x80x2-(hydroxymethyl)pyrrolidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(2xe2x80x2-(N,N-dimethylamino)ethyl)(CH3)NC(O)O-]benzyl,
4-[(2xe2x80x2-(N-methyl-N-toluene-4-sulfonylamino)ethyl)(CH3)Nxe2x80x94C(O)O-]benzyl,
4-[(2xe2x80x2-(morpholin-4xe2x80x2-yl)ethyl)(CH3)NC(O)O-]benzyl,
4-[(2xe2x80x2-(hydroxy)ethyl)(CH3)NC(O)O-]benzyl,
4-[bis(2xe2x80x2-(hydroxy)ethyl)NC(O)O-]benzyl,
4-[(2xe2x80x2-(formyloxy)ethyl)(CH3)NC(O)O-]benzyl,
4-[(CH3OC(O)CH2)HNC(O)O-]benzyl,
4-[2xe2x80x2-(phenylNHC(O)O-)ethyl-]HNC(O)O-]benzyl,
3-chloro-4-[(CH3)2NC(O)O-]benzyl,
3-chloro-4-[(4xe2x80x2-methylpiperazin-1xe2x80x2-yl)C(O)O-]benzyl,
3-chloro-4-[(4xe2x80x2-(pyridin-2-yl)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
3-chloro-4-[(thiomorpholin-4xe2x80x2-yl)C(O)O-]benzyl, and
3-fluoro-4-[(CH3)2NC(O)O-]benzyl.
In this embodiment, Ar is preferably aryl or substituted aryl and, even more preferably, is phenyl or substituted phenyl. Preferably, x is 1.
In another preferred embodiment, R3 corresponds to the R6 group, (including the preferred embodiments) found in International Patent Application Publication No. WO 98/53817 which application is incorporated herein by reference in its entirety. In this embodiment, R3 is preferably xe2x80x94CH2xe2x80x94Ar2xe2x80x94Ar1.
Preferably, in the compounds of formula Ia-b, II, IIIa,c above, R3xe2x80x2 is preferably hydrogen.
Preferably, in the compounds of formula Ia-b, II, IIIa,c above, R4 and R4xe2x80x2 are preferably hydrogen and X is preferably hydroxyl or alkoxy.
Preferably, in the compounds of formula IIIa-b, Va and VIIa above, R5 is xe2x80x94CH2xe2x80x94C(O)X, where X is as defined herein.
Preferably, in the compounds of formula IIIa-b, Va and VIIa above, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl. Even more preferably R6 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl, 2-(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4-(CH3C(O)NH-)phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, 1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4-[CH3SC(xe2x95x90NH)]phenyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1,3,4-thiadiazol-2-yl, 4-[H2NC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-yl, 4-(3xe2x80x2-dimethylamino-n-propoxy)-phenyl, and 1-methylpyrazol-4-yl.
In another preferred embodiment, R6 in the compounds of formula IIIa-b, Va and VIIb above is selected to correspond to the R1 group, including preferred embodiments, disclosed in International Patent Application Publication No. WO 98/53814 which application is incorporated herein by reference in its entirety.
In the compounds of formula IVa-b and Va-b, R14 is selected from all possible isomers arising by substitution with the following groups:
3-[(CH3)2NC(O)O-]benzyl,
4-[(CH3)2NC(O)O-]benzyl,
4-[(CH3)2NS(O)2O-]benzyl,
4-[(piperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(piperidin-4xe2x80x2-yl)C(O)O-]benzyl,
4-[(1xe2x80x2-methylpiperidin-4xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-hydroxypiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-formyloxypiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-ethoxycarbonylpiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-carboxylpiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(3xe2x80x2-hydroxymethylpiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-hydroxymethylpiperidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-phenyl-1xe2x80x2-Boc-piperidin-4xe2x80x2-yl)-C(O)O-]benzyl,
4-[(4xe2x80x2-piperidon-1xe2x80x2-yl ethylene ketal)C(O)O-]benzyl,
4-[(piperazin-4xe2x80x2-yl)-C(O)O-]benzyl,
4-[(1xe2x80x2-Boc-piperazin-4xe2x80x2-yl)-C(O)O-]benzyl,
4-[(4xe2x80x2-methylpiperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-methylhomopiperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(2-hydroxyethyl)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-phenylpiperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(pyridin-2-yl )piperazin-1xe2x80x2-yl )C(O)O-]benzyl,
4-[(4xe2x80x2-(4-trifluoromethylpyridin-2-yl)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(pyrimidin-2-yl)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-acetylpiperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(phenylC(O)-)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(pyridin-4-ylC(O)-)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(phenylNHC(O)-)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-(phenylNHC(S)-)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(4xe2x80x2-methanesulfonylpiperazin-1xe2x80x2-yl-C(O)O-)benzyl,
4-[(4xe2x80x2-trifluoromethanesulfonylpiperazin-1xe2x80x2-yl-C (O)O-)benzyl,
4-[(morpholin-4xe2x80x2-yl)C(O)O-]benzyl,
3-nitro-4-[(morpholin-4xe2x80x2-yl)-C(O)O-]benzyl,
4-[(thiomorpholin-4xe2x80x2-yl)C(O)O-]benzyl,
4-[(thiomorpholin-4xe2x80x2-yl sulfone)-C(O)O-]benzyl, (alternative nomenclature 4-[(1,1-dioxothiomorpholin-4-yl)-C(O)O-]benzyl),
4-[(pyrrolidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(2xe2x80x2-methylpyrrolidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(2xe2x80x2-(methoxycarbonyl)pyrrolidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(2xe2x80x2-(hydroxymethyl)pyrrolidin-1xe2x80x2-yl)C(O)O-]benzyl,
4-[(2xe2x80x2-(N,N-dimethylamino)ethyl)(CH3)NC(O)O-]benzyl,
4-[(2xe2x80x2-(N-methyl-N-toluene-4-sulfonylamino)ethyl)(CH3)Nxe2x80x94C(O)O-]benzyl,
4-[(2xe2x80x2-(morpholin-4xe2x80x2-yl)ethyl)(CH3)NC(O)O-]benzyl,
4-[(2xe2x80x2-(hydroxy)ethyl)(CH3)NC(O)O-]benzyl,
4-[bis(2xe2x80x2-(hydroxy)ethyl)NC(O)O-]benzyl,
4-[(2xe2x80x2-(formyloxy)ethyl)(CH3)NC(O)O-]benzyl,
4-[(CH3OC(O)CH2)HNC(O)O-]benzyl,
4-[2xe2x80x2-(phenylNHC(O)O-)ethyl-]HNC(O)O-]benzyl,
3-chloro-4-[(CH3)2NC(O)O-]benzyl,
3-chloro-4-[(4xe2x80x2-methylpiperazin-1xe2x80x2-yl)C(O)O-]benzyl,
3-chloro-4-[(4xe2x80x2-(pyridin-2-yl)piperazin-1xe2x80x2-yl)C(O)O-]benzyl,
3-chloro-4-[(thiomorpholin-4xe2x80x2-yl)C(O)O-]benzyl, and
3-fluoro-4-[(CH3)2NC(O)O-]benzyl.
In this embodiment, Ar is preferably aryl or substituted aryl and, even more preferably, is phenyl or substituted phenyl. Preferably, x is 1.
In another preferred embodiment, R14 corresponds to the R6 group, (including the preferred embodiments) found in International Patent Application Publication No. WO 98/53817 which application is incorporated herein by reference in its entirety. In this embodiment, R14 is preferably xe2x80x94CH2xe2x80x94Ar2xe2x80x94Ar1.
R15 is preferably hydrogen.
In the compounds of formula VIa-b and VII, preferred R23, R24 and R25 groups correspond to the R5, R6 and R7 groups, respectively, found in International Patent Application Publication No. WO 98/53817 which application is incorporated herein by reference in its entirety. In a preferred embodiment, in compounds of formula IVa-b and VIIa-b, R24 is xe2x80x94CH2xe2x80x94Ar2xe2x80x94Ar1 and R25 is hydrogen.
This invention also provides methods for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound of formula I-VII above under conditions wherein said compound binds to VLA-4.
Certain of the compounds of formula I-VII above are also useful in reducing VLA-4 mediated inflammation in vivo.
This invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of formula I-VII above. Preferably, R3 and R3xe2x80x2 are derived from L-amino acids or other similarly configured starting materials. Alternatively, racemic mixtures can be used.
The pharmaceutical compositions may be used to treat VLA-4 mediated disease conditions. Such disease conditions include, by way of example, asthma, Alzheimer""s disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn""s disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
Other disease conditions include, but are not limited to, inflammatory conditions such as erythema nodosum, allergic conjunctivitis, optic neuritis, uveitis, allergic rhinitis, Ankylosing spondylitis, psoriatic arthritis, vasculitis, Reiter""s syndrome, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, dermatomyositis, Wegner""s granulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporal arteritis, pericarditis, myocarditis, congestive heart failure, polyarteritis nodosa, hypersensitivity syndromes, allergy, hypereosinophilic syndromes, Churg-Strauss syndrome, chronic obstructive pulmonary disease, hypersensitivity pneumonitis, chronic active hepatitis, interstitial cystitis, autoimmune endocrine failure, primary biliary cirrhosis, autoimmune aplastic anemia, chronic persistent hepatitis and thyroiditis.
Accordingly, this invention also provides methods for the treatment of an inflammatory disease in a patient mediated by VLA-4 which methods comprise administering to the patient the pharmaceutical compositions described above.
Preferred compounds of this invention include those set forth in Table I below:
Accordingly, this invention is also directed to each of the following compounds:
N-[1-(ethoxycarbonylmethyl)benzimidazol-2-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
N-[1-(ethoxycarbonylmethyl)benzimidazol-2-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
N-(benzoxazol-2-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
N-(benzoxazol-2-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
N-(benzothiazol-2-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
N-(benzothiazol-2-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
N-(2-cyclohexylquinazol-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
N-(2-cyclohexylquinazol-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
N-[2-(piperid-1-yl)quinazol-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
N-[2-(piperid-1-yl)quinazol-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
and pharmaceutically acceptable salts thereof.
As above, this invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. However, prior to describing this invention in further detail, the following terms will first be defined.
Definitions
As used herein, xe2x80x9calkylxe2x80x9d refers to alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.
xe2x80x9cSubstituted alkylxe2x80x9d refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x9calkyl-Oxe2x80x94xe2x80x9d which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
xe2x80x9cSubstituted alkoxyxe2x80x9d refers to the group xe2x80x9csubstituted alkyl-Oxe2x80x94xe2x80x9d.
xe2x80x9cAlkenoxyxe2x80x9d refers to the group xe2x80x9calkenyl-Oxe2x80x94xe2x80x9d.
xe2x80x9cSubstituted alkenoxyxe2x80x9d refers to the group xe2x80x9csubstituted alkenyl-Oxe2x80x94xe2x80x9d.
xe2x80x9cAcylxe2x80x9d refers to the groups Hxe2x80x94C(O)xe2x80x94, alkyl-C(O)xe2x80x94, substituted alkyl-C(O)xe2x80x94, alkenyl-C(O)xe2x80x94, substituted alkenyl-C(O)xe2x80x94, alkynyl-C(O)xe2x80x94, substituted alkynyl-C(O)xe2x80x94 cycloalkyl-C(O)xe2x80x94, substituted cycloalkyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, substituted aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94, substituted heteroaryl-C(O), heterocyclic-C(O)xe2x80x94, and substituted heterocyclic-C(O)xe2x80x94 wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAcylaminoxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cThiocarbonylaminoxe2x80x9d refers to the group xe2x80x94C(S)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAcyloxyxe2x80x9d refers to the groups alkyl-C(O)Oxe2x80x94, substituted alkyl-C(O)Oxe2x80x94, alkenyl-C(O)Oxe2x80x94, substituted alkenyl-C(O)Oxe2x80x94, alkynyl-C(O)Oxe2x80x94, substituted alkynyl-C(O)Oxe2x80x94, aryl-C(O)Oxe2x80x94, substituted aryl-C(O)Oxe2x80x94, cycloalkyl-C(O)Oxe2x80x94, substituted cycloalkyl-C(O)Oxe2x80x94, heteroaryl-C(O)Oxe2x80x94, substituted heteroaryl-C(O)Oxe2x80x94, heterocyclic-C(O)Oxe2x80x94, and substituted heterocyclic-C(O)Oxe2x80x94 wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAlkenylxe2x80x9d refers to alkenyl group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation.
xe2x80x9cSubstituted alkenylxe2x80x9d refers to alkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkenyl/substituted alkenyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAlkynylxe2x80x9d refers to alkynyl group preferably having from 2 to 10 carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation.
xe2x80x9cSubstituted alkynylxe2x80x9d refers to alkynyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic,xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAmidinoxe2x80x9d refers to the group H2NC(xe2x95x90NH)xe2x80x94 and the term xe2x80x9calkylamidinoxe2x80x9d refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC(xe2x95x90NH)xe2x80x94).
xe2x80x9cThioamidinoxe2x80x9d refers to the group RSC(xe2x95x90NH)xe2x80x94 where R is hydrogen or alkyl.
xe2x80x9cAminoacylxe2x80x9d refers to the groups xe2x80x94NRC(O)alkyl, xe2x80x94NRC(O)substituted alkyl, xe2x80x94NRC(O)cycloalkyl, xe2x80x94NRC(O)substituted cycloalkyl, xe2x80x94NRC(O)alkenyl, xe2x80x94NRC(O)substituted alkenyl, xe2x80x94NRC(O)alkynyl, xe2x80x94NRC(O)substituted alkynyl, xe2x80x94NRC(O)aryl, xe2x80x94NRC(O)substituted aryl, xe2x80x94NRC(O)heteroaryl, xe2x80x94NRC(O)substituted heteroaryl, xe2x80x94NRC(O)heterocyclic, and xe2x80x94NRC(O)substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminocarbonyloxyxe2x80x9d refers to the groups xe2x80x94NRC(O)O-alkyl, xe2x80x94NRC(O)O-substituted alkyl, xe2x80x94NRC(O)O-alkenyl, xe2x80x94NRC(O)O-substituted alkenyl, xe2x80x94NRC(O)O-alkynyl, xe2x80x94NRC(O)O-substituted alkynyl, xe2x80x94NRC(O)O-cycloalkyl, xe2x80x94NRC(O)O-substituted cycloalkyl, xe2x80x94NRC(O)O-aryl, xe2x80x94NRC(O)O-substituted aryl, xe2x80x94NRC(O)O-heteroaryl, xe2x80x94NRC(O)O-substituted heteroaryl, xe2x80x94NRC(O)O-heterocyclic, and xe2x80x94NRC(O)O-substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxycarbonylaminoxe2x80x9d refers to the groups xe2x80x94OC(O)NH2, xe2x80x94OC(O)NRR, xe2x80x94OC(O)NR-alkyl, xe2x80x94OC(O)NR-substituted alkyl, xe2x80x94OC(O)NR-alkenyl, xe2x80x94OC(O)NR-substituted alkenyl, xe2x80x94OC(O)NR-alkynyl, xe2x80x94OC(O)NR-substituted alkynyl, xe2x80x94OC(O)NR-cycloalkyl, xe2x80x94OC(O)NR-substituted cycloalkyl, xe2x80x94OC(O)NR-aryl, xe2x80x94OC(O)NR-substituted aryl, xe2x80x94OC(O)NR-heteroaryl, xe2x80x94OC(O)NR-substituted heteroaryl, xe2x80x94OC(O)NR-heterocyclic, and xe2x80x94OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxythiocarbonylaminoxe2x80x9d refers to the groups xe2x80x94OC(S)NH2, xe2x80x94OC(S)NRR, xe2x80x94OC(S)NR-alkyl, xe2x80x94OC(S)NR-substituted alkyl, xe2x80x94OC(S)NR-alkenyl, xe2x80x94OC(S)NR-substituted alkenyl, xe2x80x94OC(S)NR-alkynyl, xe2x80x94OC(S)NR-substituted alkynyl, xe2x80x94OC(S)NR-cycloalkyl, xe2x80x94OC(S)NR-substituted cycloalkyl, xe2x80x94OC(S)NR-aryl, xe2x80x94OC(S)NR-substituted aryl, xe2x80x94OC(S)NR-heteroaryl, xe2x80x94OC(S)NR-substituted heteroaryl, xe2x80x94OC(S)NR-heterocyclic, and xe2x80x94OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminocarbonylaminoxe2x80x9d refers to the groups xe2x80x94NRC(O)NRR, xe2x80x94NRC(O)NR-alkyl, xe2x80x94NRC(O)NR-substituted alkyl, xe2x80x94NRC(O)NR-alkenyl, xe2x80x94NRC(O)NR-substituted alkenyl, xe2x80x94NRC(O)NR-alkynyl, xe2x80x94NRC(O)NR-substituted alkynyl, xe2x80x94NRC(O)NR-aryl, xe2x80x94NRC(O)NR-substituted aryl, xe2x80x94NRC(O)NR-cycloalkyl, xe2x80x94NRC(O)NR-substituted cycloalkyl, xe2x80x94NRC (O)NR-heteroaryl, and xe2x80x94NRC(O)NR-substituted heteroaryl, xe2x80x94NRC(O)NR-heterocyclic, and xe2x80x94NRC(O)NR-substituted heterocyclic where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminothiocarbonylaminoxe2x80x9d refers to the groups xe2x80x94NRC(S)NRR, xe2x80x94NRC(S)NR-alkyl, xe2x80x94NRC(S)NR-substituted alkyl, xe2x80x94NRC(S)NR-alkenyl, xe2x80x94NRC(S)NR-substituted alkenyl, xe2x80x94NRC(S)NR-alkynyl, xe2x80x94NRC(S)NR-substituted alkynyl, xe2x80x94NRC(S)NR-aryl, xe2x80x94NRC(S)NR-substituted aryl, xe2x80x94NRC(S)NR-cycloalkyl, xe2x80x94NRC(S)NR-substituted cycloalkyl, xe2x80x94NRC(S)NR-heteroaryl, and xe2x80x94NRC(S)NR-substituted heteroaryl, xe2x80x94NRC(S)NR-heterocyclic, and xe2x80x94NRC(S)NR-substituted heterocyclic where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cArylxe2x80x9d or xe2x80x9cArxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7yl, and the like). Preferred aryls include phenyl and naphthyl.
Substituted aryl refers to aryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 which includes, by way of example, phenoxy, naphthoxy, and the like.
xe2x80x9cSubstituted aryloxyxe2x80x9d refers to substituted aryl-Oxe2x80x94 groups.
xe2x80x9cAryloxyarylxe2x80x9d refers to the group -aryl-O-aryl.
xe2x80x9cSubstituted aryloxyarylxe2x80x9d refers to aryloxyaryl groups substituted with from 1 to 3 substituents on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cCycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Excluded from this definition are multi-ring alkyl groups such as adamantanyl, etc.
xe2x80x9cCycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 3 to 8 carbon atoms having single or multiple unsaturation but which are not aromatic.
xe2x80x9cSubstituted cycloalkylxe2x80x9d and xe2x80x9csubstituted cycloalkenylxe2x80x9d refer to a cycloalkyl and cycloalkenyl groups, preferably of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of oxo (xe2x95x90O), thioxo (xe2x95x90S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cCycloalkoxyxe2x80x9d refers to xe2x80x94O-cycloalkyl groups.
xe2x80x9cSubstituted cycloalkoxyxe2x80x9d refers to xe2x80x94O-substituted cycloalkyl groups.
xe2x80x9cCycloalkenoxyxe2x80x9d refers to xe2x80x94O-cycloalkenyl groups.
xe2x80x9cSubstituted cycloalkenoxyxe2x80x9d refers to xe2x80x94O-substituted cycloalkenyl groups.
xe2x80x9cGuanidinoxe2x80x9d refers to the groups xe2x80x94NRC(xe2x95x90NR)NRR, xe2x80x94NRC(xe2x95x90NR)NR-alkyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted alkyl, xe2x80x94NRC(xe2x95x90NR)NR-alkenyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted alkenyl, xe2x80x94NRC(xe2x95x90NR)NR-alkynyl xe2x80x94NRC(xe2x95x90NR)NR-substituted alkynyl, xe2x80x94NRC(xe2x95x90NR)NR-aryl, xe2x80x94NRC(xe2x95x90NR)NR-substituted aryl, xe2x80x94NRC(xe2x95x90NR)NR-cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NR-heteroaryl, xe2x80x94NRC(NR)NR-substituted heteroaryl, xe2x80x94NRC(xe2x95x90NR)NR-heterocyclic, and xe2x80x94NRC(xe2x95x90NR)NR-substituted heterocyclic where each R is independently hydrogen and alkyl as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cGuanidinosulfonexe2x80x9d refers to the groups xe2x80x94NRC(xe2x95x90NR)NRSO2-alkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-alkenyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkenyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-alkynyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkynyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-aryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted aryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-heteroaryl, and xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted heteroaryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-heterocyclic, and xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted heterocyclic where each R is independently hydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.
xe2x80x9cHeteroarylxe2x80x9d refers to an aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, indolyl and furyl. xe2x80x9cFused ring heteroarylxe2x80x9d refers to a heteroaryl group having two or more fused rings. Preferred fused ring heteroaryl groups include indolyl, 1H-indazolyl, benzimidizolyl, purinyl, benzoxazolyl, benzothiazolyl and the like.
xe2x80x9cSubstituted heteroarylxe2x80x9d refers to heteroaryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono-and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cHeteroaryloxyxe2x80x9d refers to the group xe2x80x94O-heteroaryl and xe2x80x9csubstituted heteroaryloxyxe2x80x9d refers to the group xe2x80x94O-substituted heteroaryl.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more of the rings can be aryl or heteroaryl. xe2x80x9cFused ring heterocyclicxe2x80x9d refers to a hetercyclic group having two or more fused rings. Preferred fused ring heterocyclic groups include indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl and the like.
xe2x80x9cSubstituted heterocyclicxe2x80x9d refers to heterocycle groups which are substituted with from 1 to 3 substituents selected from the group consisting of oxo (xe2x95x90O), thioxo (xe2x95x90S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine,, thiophene, benzo[b]thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.
xe2x80x9cHeterocyclyloxyxe2x80x9d refers to the group xe2x80x94O-heterocyclic and xe2x80x9csubstituted heterocyclyloxyxe2x80x9d refers to the group xe2x80x94O-substituted heterocyclic.
xe2x80x9cThiolxe2x80x9d refers to the group xe2x80x94SH.
xe2x80x9cThioalkylxe2x80x9d refers to the groups xe2x80x94S-alkyl.
xe2x80x9cSubstituted thioalkylxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
xe2x80x9cThiocycloalkylxe2x80x9d refers to the groups xe2x80x94S-cycloalkyl.
xe2x80x9cSubstituted thiocycloalkylxe2x80x9d refers to the group xe2x80x94S-substituted cycloalkyl.
xe2x80x9cThioarylxe2x80x9d refers to the group xe2x80x94S-aryl and xe2x80x9csubstituted thioarylxe2x80x9d refers to the group xe2x80x94S-substituted aryl.
xe2x80x9cThioheteroarylxe2x80x9d refers to the group xe2x80x94S-heteroaryl and xe2x80x9csubstituted thioheteroarylxe2x80x9d refers to the group xe2x80x94S-substituted heteroaryl.
xe2x80x9cThioheterocyclicxe2x80x9d refers to the group xe2x80x94S-heterocyclic and xe2x80x9csubstituted thioheterocyclicxe2x80x9d refers to the group xe2x80x94S-substituted heterocyclic.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
Compound Preparation
The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
Furthermore, the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
In a preferred method of synthesis, the compounds of this invention are prepared by coupling an amino acid derivative of formula 1: 
where R3, R3xe2x80x2 and X are as defined herein with a suitably functionalized fused ring heteroaryl or heterocyclic intermediate, such as a compound of formula 2: 
where R7, R8 and Y are as defined herein, to form a coupled reaction product, such as a compound of formula 3: 
This reaction is typically conducted by contacting one molar equivalent of the heteroaryl or heterocyclic intermediate, such as 2, with at least one molar equivalent of the amino acid derivative 1 in an inert diluent, such as DMSO, at a temperature ranging from about 60xc2x0 C. to about 250xc2x0 C. for about 12 to about 48 hours. Upon completion of the reaction, the resulting coupled product 3 is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like. In addition to the chloro derivative 2, heteroaryl intermediates having other suitable leaving groups, such as bromo, iodo, tosyl, mesyl and the like, may also be employed in the coupling reaction.
The amino acid derivatives 1 employed in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. For example, amino acid derivatives can be prepared by C-alkylating commercially available diethyl 2-acetamidomalonate (Aldrich, Milwaukee, Wis., USA) with an alkyl or substituted alkyl halide. This reaction is typically conducted by treating the diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl or substituted alkyl halide in refluxing ethanol for about 6 to about 12 hours. The resulting C-alkylated malonate is then deacetylated, hydrolyzed and decarboxylated by heating in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to provide the amino acid, typically as the hydrochloride salt.
Examples of amino acid derivatives of formula 1 suitable for use in the above reactions include, but are not limited to, L-tyrosine methyl ester, L-3,5-diiodotyrosine methyl ester, L-3-iodotyrosine methyl ester, xcex2-(4-hydroxy-naphth-1-yl)-L-alanine methyl ester, xcex2-(6-hydroxy-naphth-2-yl)-L-alanine methyl ester, L-4-(N,N-dimethylcarbamyloxy)phenylalanine ethyl ester and the like. If desired, of course, other esters or amides of the above-described compounds may also be employed.
Similarly, the heteroaryl or heterocyclic intermediates employed in the coupling reaction are either commercially available or can be prepared from commercially available starting materials using procedures and reagents well-known in the art. For example, the synthesis of 2-chloro-3-nitroquinoline is described in Chem. Pharm. Bull. 1959, 7, 273. Preferred heteroaryl intermediates for use in this reaction include 2-chlorobenzimidazole derivatives, 2-chlorobenzoxazole derivatives, 2-chlorobenzothiazole derivatives and 4-chloroquinazoline derivatives.
When compound 2 is a 2-chlorobenzimidazole derivative (i.e., Y is xe2x80x94NHxe2x80x94), the nitrogen atom can be readily alkylated, if desired, prior to coupling with amino acid derivative 1. Typically, this alkylation reaction is conducted by contacting the 2-chlorobenzimidazole with a base, such as potassium carbonate, in the presence of an alkylating agent, such as ethyl chloroacetate, in an inert diluent at a temperature ranging from about 0xc2x0 C. to about 100xc2x0 C. for about 6 to about 48 hours. The alkylated product is then employed in the above described coupling reaction.
Alternatively, a 2-chlorobenzimidazole derivative can be sulfonated prior to the coupling reaction by reacting 2 with a sulfonyl chloride of the formula: R6xe2x80x94S(O)2xe2x80x94Cl, where R6 is as defined herein, to provide a sulfonamide intermediate. This reaction is typically conducted by reacting the 2-chlorobenzimidazole derivative with at least one equivalent, preferably about 1.1 to about 2 equivalents, of a sulfonyl chloride in an inert diluent such as dichloromethane and the like. Generally, the reaction is conducted at a temperature ranging from about xe2x88x9270xc2x0 C. to about 40xc2x0 C. for about 1 to about 24 hours. Preferably, this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like, as the base. Upon completion of the reaction, the resulting sulfonamide is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.
The sulfonyl chlorides employed in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Such compounds are typically prepared from the corresponding sulfonic acid, i.e., from compounds of the formula R6xe2x80x94SO3H where R6 is as defined above, using phosphorous trichloride and phosphorous pentachloride. This reaction is generally conducted by contacting the sulfonic acid with about 2 to 5 molar equivalents of phosphorous trichloride and phosphorous pentachloride, either neat or in an inert solvent, such as dichloromethane, at temperature in the range of about 0xc2x0 C. to about 80xc2x0 C. for about 1 to about 48 hours to afford the sulfonyl chloride. Alternatively, the sulfonyl chloride can be prepared from the corresponding thiol compound, i.e., from compounds of the formula R6xe2x80x94SH where R6 is as defined herein, by treating the thiol with chlorine (Cl2) and water under conventional reaction conditions.
Examples of sulfonyl chlorides suitable for use in this invention include, but are not limited to, methanesulfonyl chloride, 2-propanesulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-toluenesulfonyl chloride, xcex1-toluenesulfonyl chloride, 4-acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride, 4-tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 2-carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride, 3,4-dichlorobenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonyl chloride, 3,4-dimethoxybenzenesulfonyl chloride, 3,5-ditrifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2-methoxycarbonylbenzenesulfonyl chloride, 4-methylamidobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonyl chloride, 4-trifluoromethylbenzenesulfonyl chloride, 4-trifluoromethoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonyl chloride, 2-thiophenesulfonyl chloride, 5-chloro-2-thiophenesulfonyl chloride, 2,5-dichloro-4-thiophenesulfonyl chloride, 2-thiazolesulfonyl chloride, 2-methyl-4-thiazolesulfonyl chloride, 1-methyl-4-imidazolesulfonyl chloride, 1-methyl-4-pyrazolesulfonyl chloride, 5-chloro-1,3-dimethyl-4-pyrazolesulfonyl chloride, 3-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride and the like. If desired, a sulfonyl fluoride, sulfonyl bromide or sulfonic acid anhydride may be used in place of the sulfonyl chloride in the above reaction to form the sulfonamide intermediate 5.
In another preferred embodiment, compounds of this invention may be prepared by displacement of a leaving group as shown in Scheme 1: 
where R3, Q and X are as defined herein; Axe2x80x2 is heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Bxe2x80x2 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic; and L1 is a leaving group, such as chloro, bromo, iodo, sulfonate ester and the like.
Typically, this reaction is conducted by combining approximately stoichiometric equivalents of 4 and 5 in a suitable inert diluent such as water, dimnethylsulfoxide (DMSO) and the like, with an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to scavenge the acid generated by the reaction. The reaction is preferably conducted at from about 25xc2x0 C. to about 100xc2x0 C. until reaction completion which typically occurs within 1 to about 24 hours. This reaction is further described in U.S. Pat. No. 3,598,859, which is incorporated herein by reference in its entirety. Upon reaction completion, the product 6 is recovered by conventional methods including precipitation, chromatography, filtration and the like.
In still another alternative embodiment, compounds of this invention in which Q is NR4 can be prepared by reductive amination of a suitable 2-oxocarboxylic acid ester, 8, such as a pyruvate ester, as shown in Scheme 2: 
where Axe2x80x2, Bxe2x80x2, R3 and X are as defined herein.
Generally, this reaction is conducted by combining equamolar amounts of 7 and 8 in an inert diluent such as methanol, ethanol and the like under conditions which provide for imine formation (not shown). The imine formed is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H2/palladium on carbon and the like to form the product 9. In a particularly preferred embodiment, the reducing agent is H2/palladium on carbon which is incorporated into the initial reaction medium thereby permitting imine reduction in situ in a one pot procedure to provide 9. The reaction is preferably conducted at from about 20xc2x0 C. to about 80xc2x0 C. at a pressure of from 1 to 10 atmospheres until reaction completion which typically occurs within 1 to about 24 hours. Upon reaction completion, the product 9 is recovered by conventional methods including chromatography, filtration and the like.
Alternatively, certain compounds of this invention can be prepared via a rhodium-catalyzed insertion reaction as shown in Scheme 3: 
where Axe2x80x2, Bxe2x80x2, R3 and X (preferably alkoxy) are as defined herein. Typically, this reaction is conducted using rhodium acetate dimer, Rh2(OAc)4, in an inert diluent such as toluene at a temperature ranging from about 25xc2x0 C. to about 80xc2x0 C. for about 1 to 12 hours to afford 12. This reaction is described further in B. R. Henke et. al., J. Med. Chem. 1998, 41, 5020-5036 and references cited therein.
Similarly, certain compounds of this invention can be prepared by the copper-catalyzed coupling reaction shown in Scheme 4: 
where Axe2x80x2, Bxe2x80x2, R3 and X (preferably alkoxy) are as defined herein, and X3 is halogen, such as chloro, bromo or iodo (preferably iodo). Typically, this reaction is conducted using copper iodide (CuI) and potassium carbonate in an inert diluent such as N,N-dimethyl acetamide (DMA) at a temperature ranging from about 60xc2x0 C. to about 120xc2x0 C. for about 12 to 36 hours to afford 12. This reaction is described further in D. Ma et. al., J. Am. Chem. Soc. 1998, 120, 12459-12467 and references cited therein.
For ease of synthesis, the compounds of formula I-VII are typically prepared as an ester, i.e., where X is an alkoxy or substituted alkoxy group and the like. If desired, the ester group can be hydrolysed using conventional conditions and reagents to provide the corresponding carboxylic acid. Typically, this reaction is conducted by treating the ester with at least one equivalent of an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, in an inert diluent, such as methanol or mixtures of methanol and water, at a temperature ranging about 0xc2x0 C. to about 24xc2x0 C. for about 1 to about 12 hours. Alternatively, benzyl esters may be removed by hydrogenolysis using a palladium catalyst, such as palladium on carbon, and tert-butyl esters can be removed using formic acid to afford the corresponding carboxylic acid.
As will be apparent to those skilled in the art, other functional groups present on any of the substituents of the compounds of formula I-VII, in addition to the carbamate-type functionality, can be readily modified or derivatized either before or after the above-described synthetic reactions using well-known synthetic procedures. For example, a nitro group present on a substituent of a compound of formula I-VII or an intermediate thereof may be readily reduced by hydrogenation in the presence of a palladium catalyst, such as palladium on carbon, to provide the corresponding amino group. This reaction is typically conducted at a temperature of from about 20xc2x0 C. to about 50xc2x0 C. for about 6 to about 24 hours in an inert diluent, such as methanol. Compounds having a nitro group on the R3 and/or R3xe2x80x2 substituent can be prepared, for example, by using a 4-nitrophenylalanine derivative and the like in the above-described coupling reactions.
Similarly, a pyridyl group can be hydrogenated in the presence of a platinum catalyst, such as platinum oxide, in an acidic diluent to provide the corresponding piperidinyl analogue. Generally, this reaction is conducted by treating the pyridine compound with hydrogen at a pressure ranging from about 20 psi to about 60 psi, preferably about 40 psi, in the presence of the catalyst at a temperature of about 20xc2x0 C. to about 50xc2x0 C. for about 2 to about 24 hours in an acidic diluent, such as a mixture of methanol and aqueous hydrochloric acid.
Additionally, when the R3 and/or R3xe2x80x2 substituent of a compound of formula I-VII or an intermediate thereof contains a primary or secondary amino group, such amino groups can be further derivatized either before or after the above coupling reactions to provide (in addition to the carbamate-type functionality), by way of example, amides, sulfonamides, ureas, thioureas, carbamates, secondary or tertiary amines and the like. Compounds having a primary amino group on the R3 and/or R3xe2x80x2 substituent may be prepared, for example, by reduction of the corresponding nitro compound as described above.
By way of illustration, a compound of formula I-VII or an intermediate thereof having a substituent containing a primary or secondary amino group, such as where R3 is a (4-aminophenyl)methyl group, can be readily N-acylated using conventional acylating reagents and conditions to provide the corresponding amide. This acylation reaction is typically conducted by treating the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of a carboxylic acid in the presence of a coupling reagent such as a carbodiimide, BOP reagent (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphonate) and the like, in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylformamide and the like, at a temperature ranging from about 0xc2x0 C. to about 37xc2x0 C. for about 4 to about 24 hours. Preferably, a promoter, such as N-hydroxysuccinimide, 1-hydroxy-benzotriazole and the like, is used to facilitate the acylation reaction. Examples of carboxylic acids suitable for use in this reaction include, but are not limited to, N-tert-butyloxycarbonylglycine, N-tert-butyloxycarbonyl-L-phenylalanine, N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid, N-tert-butyloxycarbonylisonipecotic acid, N-methylisonipecotic acid, N-tert-butyloxycarbonylnipecotic acid, N-tert-butyloxycarbonyl-L-tetrahydroisoquinoline-3-carboxylic acid, N-(toluene-4-sulfonyl)-L-proline and the like.
Alternatively, a compound of formula I-VII or an intermediate thereof containing a primary or secondary amino group can be N-acylated using an acyl halide or a carboxylic acid anhydride to form the corresponding amide. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the acyl halide or carboxylic acid anhydride in an inert diluent, such as dichloromethane, at a temperature ranging from about xe2x88x9270xc2x0 C. to about 40xc2x0 C. for about 1 to about 24 hours. If desired, an acylation catalyst such as 4-(N,N-dimethylamino)pyridine may be used to promote the acylation reaction. The acylation reaction is preferably conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like.
Examples of acyl halides and carboxylic acid anhydrides suitable for use in this reaction include, but are not limited to, 2-methylpropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-trifluoro-methylbenzoyl chloride, isonicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride, and the like. Carbamyl chlorides, such as N,N-dimethylcarbamyl chloride, N,N-diethylcarbamyl chloride and the like, can also be used in this reaction to provide ureas. Similarly, dicarbonates, such as di-tert-butyl dicarbonate, may be employed to provide carbamates.
In a similar manner, a compound of formula I-VII or an intermediate thereof containing a primary or secondary amino group may be N-sulfonated to form a sulfonamide using a sulfonyl halide or a sulfonic acid anhydride. Sulfonyl halides and sulfonic acid anhydrides suitable for use in this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. Similarly, sulfamoyl chlorides, such as dimethylsulfamoyl chloride, can be used to provide sulfamides (e.g.,  greater than Nxe2x80x94SO2xe2x80x94N less than ).
Additionally, a primary and secondary amino group present on a substituent of a compound of formula I-VII or an intermediate thereof can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea, respectively. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as toluene and the like, at a temperature ranging from about 24xc2x0 C. to about 37xc2x0 C. for about 12 to about 24 hours. The isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from commercially available compounds using well-known synthetic procedures. For example, isocyanates and thioisocyanates are readily prepared by reacting the appropriate amine with phosgene or thiophosgene. Examples of isocyanates and thioisocyanates suitable for use in this reaction include, but are not limited to, ethyl isocyanate, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methyl thioisocyanate, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3-phenylpropyl thioisocyanate, 3-(N,N-diethylamino)propyl thioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate, fluorescein isothiocyanate (isomer I) and the like.
Furthermore, when a compound of formula I-VII or an intermediate thereof contains a primary or secondary amino group, the amino group can be reductively alkylated using aldehydes or ketones to form a secondary or tertiary amino group. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of an aldehyde or ketone and at least one equivalent based on the amino compound of a metal hydride reducing agent, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures thereof and the like, at a temperature ranging from about 0xc2x0 C. to about 50xc2x0 C. for about 1 to about 72 hours. Aldehydes and ketones suitable for use in this reaction include, by way of example, benzaldehyde, 4-chlorobenzaldehyde, valeraldehyde and the like.
In a similar manner, when a compound of formula I-VII or an intermediate thereof has a substituent containing a hydroxyl group, the hydroxyl group can be further modified or derivatized either before or after the above coupling reactions to provide, by way of example, ethers, carbamates and the like. Compounds having a hydroxyl group on the R3 substituent, for example, can be prepared using an amino acid derivative derived from tyrosine and the like in the above-described reactions.
By way of example, a compound of formula I-VII or an intermediate thereof having a substituent containing a hydroxyl group, such as where R3 is a (4-hydroxyphenyl)methyl group, can be readily O-alkylated to form ethers. This O-alkylation reaction is typically conducted by contacting the hydroxy compound with a suitable alkali or alkaline earth metal base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, to form the alkali or alkaline earth metal salt of the hydroxyl group. This salt is generally not isolated, but is reacted in situ with at least one equivalent of an alkyl or substituted alkyl halide or sulfonate, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, to afford the ether. Generally, this reaction is conducted at a temperature ranging from about 60xc2x0 C. to about 150xc2x0 C. for about 24 to about 72 hours. Preferably, a catalytic amount of sodium or potassium iodide is added to the reaction mixture when an alkyl chloride or bromide is employed in the reaction.
Examples of alkyl or substituted alkyl halides and sulfonates suitable for use in this reaction include, but are not limited to, tert-butyl bromoacetate, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl xcex1-bromophenylacetate, 2-(N-ethyl-N-phenylamino)ethyl chloride, 2-(N,N-ethylamino)ethyl chloride, 2-(N,N-diisopropylamino)ethyl chloride, 2-(N,N-dibenzylamino)ethyl chloride, 3-(N,N-ethylamino)propyl chloride, 3-(N-benzyl-N-methylamino)propyl chloride, N-(2-chloroethyl)morpholine, 2-(hexamethyleneimino)ethyl chloride, 3-(N-methylpiperazine)propyl chloride, 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine, 2-(4-hydroxy-4-phenylpiperidine)ethyl chloride, N-tert-butyloxycarbonyl-3-piperidinemethyl tosylate, and the like.
Alternatively, a hydroxyl group present on a substituent of a compound of formula I-VII or an intermediate thereof can be O-alkylating using the Mitsunobu reaction. In this reaction, an alcohol, such as 3-(N,N-dimethylamino)-1-propanol and the like, is reacted with about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about xe2x88x9210xc2x0 C. to about 5xc2x0 C. for about 0.25 to about 1 hour. About 1.0 to about 1.3 equivalents of a hydroxy compound, such as N-tert-butyltyrosine methyl ester, is then added and the reaction mixture is stirred at a temperature of about 0xc2x0 C. to about 30xc2x0 C. for about 2 to about 48 hours to provide the O-alkylated product.
In a similar manner, a compound of formula I-VII or an intermediate thereof containing an aryl hydroxy group can be reacted with an aryl iodide to provide a diaryl ether. Generally, this reaction is conducted by forming the alkali metal salt of the hydroxyl group using a suitable base, such as sodium hydride, in an inert diluent such as xylenes at a temperature of about xe2x88x9225xc2x0 C. to about 10xc2x0 C. The salt is then treated with about 1.1 to about 1.5 equivalents of cuprous bromide dimethyl sulfide complex at a temperature ranging from about 10xc2x0 C. to about 30xc2x0 C. for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate and the like. The reaction is then heated to about 70xc2x0 C. to about 150xc2x0 C. for about 2 to about 24 hours to provide the diaryl ether.
Additionally, a hydroxy-containing compound can also be readily derivatized to form a carbamate. In one method for preparing such carbamates, a hydroxy compound of formula I-VII or an intermediate thereof is contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent, such as dichloromethane, at a temperature ranging from about xe2x88x9225xc2x0 C. to about 0xc2x0 C. for about 0.5 to about 2.0 hours. Treatment of the resulting carbonate with an excess, preferably about 2 to about 5 equivalents, of a trialkylamine, such as triethylamine, for about 0.5 to 2 hours, followed by about 1.0 to about 1.5 equivalents of a primary or secondary amine provides the carbamate. Examples of amines suitable for using in this reaction include, but are not limited to, piperazine, 1-methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine, pyrrolidine, piperidine and the like.
Alternatively, in another method for preparing carbamates, a hydroxy-containing compound is contacted with about 1.0 to about 1.5 equivalents of a carbamyl chloride in an inert diluent, such as dichloromethane, at a temperature ranging from about 25xc2x0 C. to about 70xc2x0 C. for about 2 to about 72 hours. Typically, this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Additionally, at least one equivalent (based on the hydroxy compound) of 4-(N,N-dimethylamino)pyridine is preferably added to the reaction mixture to facilitate the reaction. Examples of carbamyl chlorides suitable for use in this reaction include, by way of example, dimethylcarbamyl chloride, diethylcarbamyl chloride and the like.
Likewise, when a compound of formula I-VII or an intermediate thereof contains a primary or secondary hydroxyl group, such hydroxyl groups can be readily converted into a leaving group and displaced to form, for example, amines, sulfides and fluorides. Generally, when a chiral compound is employed in these reactions, the stereochemistry at the carbon atom attached to the derivatized hydroxyl group is typically inverted.
These reactions are typically conducted by first converting the hydroxyl group into a leaving group, such as a tosylate, by treatment of the hydroxy compound with at least one equivalent of a sulfonyl halide, such as p-toluenesulfonyl chloride and the like, in pyridine. This reaction is generally conducted at a temperature of from about 0xc2x0 C. to about 70xc2x0 C. for about 1 to about 48 hours. The resulting tosylate can then be readily displaced with sodium azide, for example, by contacting the tosylate with at least one equivalent of sodium azide in an inert diluent, such as a mixture of N,N-dimethylformamide and water, at a temperature ranging from about 0xc2x0 C. to about 37xc2x0 C. for about 1 to about 12 hours to provide the corresponding azido compound. The azido group can then be reduced by, for example, hydrogenation using a palladium on carbon catalyst to provide the amino (xe2x80x94NH2) compound.
Similarly, a tosylate group can be readily displaced by a thiol to form a sulfide. This reaction is typically conducted by contacting the tosylate with at least one equivalent of a thiol, such as thiophenol, in the presence of a suitable base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in an inert diluent, such as N,N-dimethylformamide, at a temperature of from about 0xc2x0 C. to about 37xc2x0 C. for about 1 to about 12 hours to provide the sulfide. Additionally, treatment of a tosylate with morpholinosulfur trifluoride in an inert diluent, such as dichloromethane, at a temperature ranging from about 0xc2x0 C. to about 37xc2x0 C. for about 12 to about 24 hours affords the corresponding fluoro compound.
Furthermore, a compound of formula I-VII or an intermediate thereof having a substituent containing an iodoaryl group, for example, when R3 is a (4-iodophenyl)methyl group, can be readily converted either before or after the above coupling reactions into a biaryl compound. Typically, this reaction is conducted by treating the iodoaryl compound with about 1.1 to about 2 equivalents of an arylzinc iodide, such as 2-(methoxycarbonyl)phenylzinc iodide, in the presence of a palladium catalyst, such as palladium tetra(triphenylphosphine), in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about 24xc2x0 C. to about 30xc2x0 C. until reaction completion. This reaction is further described, for example, in Rieke, J. Org. Chem. 1991, 56, 1445. Additional methods for preparing biaryl derivatives are disclosed in International Publication Number WO 98/53817, published Dec. 3, 1998, the disclosure of which is incorporated herein by reference in its entirety.
In some cases, the compounds of formula I-VII or intermediates thereof may contain substituents having one or more sulfur atoms. When present, such sulfur atoms can be oxidized either before or after the above coupling reactions to provide a sulfoxide or sulfone compound using conventional reagents and reaction conditions. Suitable reagents for oxidizing a sulfide compound to a sulfoxide include, by way of example, hydrogen peroxide, 3-chloroperoxybenzoic acid (MCPBA), sodium periodate and the like. The oxidation reaction is typically conducted by contacting the sulfide compound with about 0.95 to about 1.1 equivalents of the oxidizing reagent in an inert diluent, such as dichloromethane, at a temperature ranging from about xe2x88x9250xc2x0 C. to about 75xc2x0 C. for about 1 to about 24 hours. The resulting sulfoxide can then be further oxidized to the corresponding sulfone by contacting the sulfoxide with at least one additional equivalent of an oxidizing reagent, such as hydrogen peroxide, MCPBA, potassium permanganate and the like. Alternatively, the sulfone can be prepared directly by contacting the sulfide with at least two equivalents, and preferably an excess, of the oxidizing reagent. Such reactions are described further in March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th Ed., pp. 1201-1202, Wiley Publisher, 1992.
Other procedures and reaction conditions for preparing the compounds of this invention are described in the examples set forth below.
Pharmaceutical Formulations
When employed as pharmaceuticals, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I-VII above associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient""s symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The following formulation examples illustrate the pharmaceutical compositions of the present invention.
Hard gelatin capsules containing the following ingredients are prepared:
The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
A tablet formula is prepared using the ingredients below:
The compound are blended and compressed to form tablets, each weighing 240 mg.
A dry powder inhaler formulation is prepared containing the following components:
The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
Tablets, each containing 30 mg of active ingredient, are prepared as follows:
The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 to 60xc2x0 C. and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Capsules, each containing 40 mg of medicament are made as follows:
The active ingredient, cellulose, starch, an magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
Suppositories, each containing 25 mg of active ingredient are made as follows:
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows:
The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 mg quantities.
An intravenous formulation may be prepared as follows:
A topical formulation may be prepared as follows:
The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices (xe2x80x9cpatchesxe2x80x9d). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See. e.g., U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Direct or indirect placement techniques may be used when it is desirable or necessary to introduce the pharmaceutical composition to the brain. Direct techniques usually involve placement of a drug delivery catheter into the host""s ventricular system to bypass the blood-brain barrier. One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Pat. No. 5,011,472 which is herein incorporated by reference.
Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
Utility
The compounds of this invention can be employed to bind VLA-4 (xcex14xcex21 integrin) in biological samples and, accordingly have utility in, for example, assaying such samples for VLA-4. In such assays, the compounds can be bound to a solid support and the VLA-4 sample added thereto. The amount of VLA-4 in the sample can be determined by conventional methods such as use of a sandwich ELISA assay. Alternatively, labeled VLA-4 can be used in a competitive assay to measure for the presence of VLA-4 in the sample. Other suitable assays are well known in the art.
In addition, certain of the compounds of this invention inhibit, in vivo, adhesion of leukocytes to endothelial cells mediated by VLA-4 and, accordingly, can be used in the treatment of diseases mediated by VLA-4. Such diseases include inflammatory diseases in mammalian patients such as asthma, Alzheimer""s disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn""s disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
The biological activity of the compounds identified above may be assayed in a variety of systems. For example, a compound can be immobilized on a solid surface and adhesion of cells expressing VLA-4 can be measured. Using such formats, large numbers of compounds can be screened. Cells suitable for this assay include any leukocytes known to express VLA-4 such as T cells, B cells, monocytes, eosinophils, and basophils. A number of leukocyte cell lines can also be used, examples include Jurkat and U937.
The test compounds can also be tested for the ability to competitively inhibit binding between VLA-4 and VCAM-1, or between VLA-4 and a labeled compound known to bind VLA-4 such as a compound of this invention or antibodies to VLA-4. In these assays, the VCAM-1 can be immobilized on a solid surface. VCAM-1 may also be expressed as a recombinant fusion protein having an Ig tail (e.g., IgG) so that binding to VLA-4 may be detected in an immunoassay. Alternatively, VCAM-1, expressing cells, such as activated endothelial cells or VCAM-1 transfected fibroblasts can be used. For assays to measure the ability to block adhesion to brain endothelial cells, the assays described in International Patent Application Publication No. WO 91/05038 are particularly preferred. This application is incorporated herein by reference in its entirety.
Many assay formats employ labelled assay components. The labelling systems can be in a variety of forms. The label may be coupled directly or indirectly to the desired component of the assay according to methods well known in the art. A wide variety of labels may be used. The component may be labelled by any one of several methods. The most common method of detection is the use of autoradiography with 3H, 125I, 35S, 14C, or 32P labelled compounds or the like. Non-radioactive labels include ligands which bind to labelled antibodies, fluorophores, chemiluminescent agents, enzymes and antibodies which can serve as specific binding pair members for a labelled ligand. The choice of label depends on sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation.
Appropriate in vivo models for demonstrating efficacy in treating inflammatory responses include EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs or primates, as well as other inflammatory models dependent upon xcex14 integrins.
Compounds having the desired biological activity may be modified as necessary to provide desired properties such as improved pharmacological properties (e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications. For instance, inclusion of one or more D-amino acids in the sulfonamides of this invention typically increases in vivo stability. Stability can be assayed in a variety of ways such as by measuring the half-life of the proteins during incubation with peptidases or human plasma or serum. A number of such protein stability assays have been described (see, e.g., Verhoef et al., Eur. J. Drug Metab. Pharmacokinet., 1990, 15(2):83-93).
For diagnostic purposes, a wide variety of labels may be linked to the compounds, which may provide, directly or indirectly, a detectable signal. Thus, the compounds of the subject invention may be modified in a variety of ways for a variety of end purposes while still retaining biological activity. In addition, various reactive sites may be introduced at the terminus for linking to particles, solid substrates, macromolecules, or the like.
Labeled compounds can be used in a variety of in vivo or in vitro applications. A wide variety of labels may be employed, such as radionuclides (e.g., gamma-emitting radioisotopes such as technetium-99 or indium-111), fluorescers (e.g., fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like. Those of ordinary skill in the art will know of other suitable labels for binding to the complexes, or will be able to ascertain such using routine experimentation. The binding of these labels is achieved using standard techniques common to those of ordinary skill in the art.
In vitro uses include diagnostic applications such as monitoring inflammatory responses by detecting the presence of leukocytes expressing VLA-4. The compounds of this invention can also be used for isolating or labeling such cells. In addition, as mentioned above, the compounds of the invention can be used to assay for potential inhibitors of VLA-4/VCAM-1 interactions.
For in vivo diagnostic imaging to identify, e.g., sites of inflammation, radioisotopes are typically used in accordance with well known techniques. The radioisotopes may be bound to the peptide either directly or indirectly using intermediate functional groups. For instance, chelating agents such as diethylenetriaminepentacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) and similar molecules have been used to bind proteins to metallic ion radioisotopes.
The complexes can also be labeled with a paramagnetic isotope for purposes of in vivo diagnosis, as in magnetic resonance imaging (MRI) or electron spin resonance (ESR), both of which are well known. In general, any conventional method for visualizing diagnostic imaging can be used. Usually gamma- and positron-emitting radioisotopes are used for camera imaging and paramagnetic isotopes are used for MRI. Thus, the compounds can be used to monitor the course of amelioration of an inflammatory response in an individual. By measuring the increase or decrease in lymphocytes expressing VLA-4 it is possible to determine whether a particular therapeutic regimen aimed at ameliorating the disease is effective.
The pharmaceutical compositions of the present invention can be used to block or inhibit cellular adhesion associated with a number of diseases and disorders. For instance, a number of inflammatory disorders are associated with integrins or leukocytes. Treatable disorders include, e.g., transplantation rejection (e.g., allograft rejection), Alzheimer""s disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), retinitis, cancer metastases, rheumatoid arthritis, acute leukocyte-mediated lung injury (e.g., adult respiratory distress syndrome), asthma, nephritis, and acute and chronic inflammation, including atopic dermatitis, psoriasis, myocardial ischemia, and inflammatory bowel disease (including Crohn""s disease and ulcerative colitis). In preferred embodiments the pharmaceutical compositions are used to treat inflammatory brain disorders, such as multiple sclerosis (MS), viral meningitis and encephalitis.
Inflammatory bowel disease is a collective term for two similar diseases referred to as Crohn""s disease and ulcerative colitis. Crohn""s disease is an idiopathic, chronic ulceroconstrictive inflammatory disease characterized by sharply delimited and typically transmural involvement of all layers of the bowel wall by a granulomatous inflammatory reaction. Any segment of the gastrointestinal tract, from the mouth to the anus, may be involved, although the disease most commonly affects the terminal ileum and/or colon. Ulcerative colitis is an inflammatory response limited largely to the colonic mucosa and submucosa. Lymphocytes and macrophages are numerous in lesions of inflammatory bowel disease and may contribute to inflammatory injury.
Asthma is a disease characterized by increased responsiveness of the tracheobronchial tree to various stimuli potentiating paroxysmal constriction of the bronchial airways. The stimuli cause release of various mediators of inflammation from IgE-coated mast cells including histamine, eosinophilic and neutrophilic chemotactic factors, leukotrines, prostaglandin and platelet activating factor. Release of these factors recruits basophils, eosinophils and neutrophils, which cause inflammatory injury.
Atherosclerosis is a disease of arteries (e.g., coronary, carotid, aorta and iliac). The basic lesion, the atheroma, consists of a raised focal plaque within the intima, having a core of lipid and a covering fibrous cap. Atheromas compromise arterial blood flow and weaken affected arteries. Myocardial and cerebral infarcts are a major consequence of this disease. Macrophages and leukocytes are recruited to atheromas and contribute to inflammatory injury.
Rheumatoid arthritis is a chronic, relapsing inflammatory disease that primarily causes impairment and destruction of joints. Rheumatoid arthritis usually first affects the small joints of the hands and feet but then may involve the wrists, elbows, ankles and knees. The arthritis results from interaction of synovial cells with leukocytes that infiltrate from the circulation into the synovial lining of the joints. See e.g., Paul, Immunology (3d ed., Raven Press, 1993).
Another indication for the compounds of this invention is in treatment of organ or graft rejection mediated by VLA-4. Over recent years there has been a considerable improvement in the efficiency of surgical techniques for transplanting tissues and organs such as skin, kidney, liver, heart, lung, pancreas and bone marrow. Perhaps the principal outstanding problem is the lack of satisfactory agents for inducing immunotolerance in the recipient to the transplanted allograft or organ. When allogeneic cells or organs are transplanted into a host (i.e., the donor and donee are different individuals from the same species), the host immune system is likely to mount an immune response to foreign antigens in the transplant (host-versus-graft disease) leading to destruction of the transplanted tissue. CD8+ cells, CD4 cells and monocytes are all involved in the rejection of transplant tissues. Compounds of this invention which bind to alpha-4 integrin are useful, inter alia, to block alloantigen-induced immune responses in the donee thereby preventing such cells from participating in the destruction of the transplanted tissue or organ. See, e.g., Paul et al., Transplant International 9, 420-425 (1996); Georczynski et al., Immunology 87, 573-580 (1996); Georcyznski et al., Transplant. Immunol. 3, 55-61 (1995); Yang et al., Transplantation 60, 71-76 (1995); Anderson et al., APMIS 102, 23-27 (1994).
A related use for compounds of this invention which bind to VLA-4 is in modulating the immune response involved in xe2x80x9cgraft versus hostxe2x80x9d disease (GVHD). See e.g., Schlegel et al., J. Immunol. 155, 3856-3865 (1995). GVHD is a potentially fatal disease that occurs when immunologically competent cells are transferred to an allogeneic recipient. In this situation, the donor""s immunocompetent cells may attack tissues in the recipient. Tissues of the skin, gut epithelia and liver are frequent targets and may be destroyed during the course of GVHD. The disease presents an especially severe problem when immune tissue is being transplanted, such as in bone marrow transplantation; but less severe GVHD has also been reported in other cases as well, including heart and liver transplants. The therapeutic agents of the present invention are used, inter alia, to block activation of the donor T-cells thereby interfering with their ability to lyse target cells in the host.
A further use of the compounds of this invention is inhibiting tumor metastasis. Several tumor cells have been reported to express VLA-4 and compounds which bind VLA-4 block adhesion of such cells to endothelial cells. Steinback et al., Urol. Res. 23, 175-83 (1995); Orosz et al., Int. J. Cancer 60, 867-71 (1995); Freedman et al., Leuk. Lymphoma 13, 47-52 (1994); Okahara et al., Cancer Res. 54, 3233-6 (1994).
A further use of the compounds of this invention is in treating multiple sclerosis. Multiple sclerosis is a progressive neurological autoimmune disease that affects an estimated 250,000 to 350,000 people in the United States. Multiple sclerosis is thought to be the result of a specific autoimmune reaction in which certain leukocytes attack and initiate the destruction of myelin, the insulating sheath covering nerve fibers. In an animal model for multiple sclerosis, murine monoclonal antibodies directed against VLA-4 have been shown to block the adhesion of leukocytes to the endothelium, and thus prevent inflammation of the central nervous system and subsequent paralysis in the animals16.
Pharmaceutical compositions of the invention are suitable for use in a variety of drug delivery systems. Suitable formulations for use in the present invention are found in Remington""s Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, Pa., 17th ed. (1985).
In order to enhance serum half-life, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds. A variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al., U.S. Pat. Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference.
The amount administered to the patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions are administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as xe2x80x9ctherapeutically effective dose.xe2x80x9d Amounts effective for this use will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the inflammation, the age, weight and general condition of the patient, and the like.
The compositions administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
The therapeutic dosage of the compounds of the present invention will vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. For example, for intravenous administration, the dose will typically be in the range of about 20 xcexcg to about 500 xcexcg per kilogram body weight, preferably about 100 xcexcg to about 300 xcexcg per kilogram body weight. Suitable dosage ranges for intranasal administration are generally about 0.1 pg to 1 mg per kilogram body weight. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
Compounds of this invention are also capable of binding or antagonizing the actions of xcex16xcex21, xcex19xcex21, xcex14xcex27, xcex1dxcex22, xcex1excex27 integrins (although xcex14xcex21, and xcex19xcex21 are preferred in this invention). Accordingly, compounds of this invention are also useful for preventing or reversing the symptoms, disorders or diseases induced by the binding of these integrins to their respective ligands.
For example, International Publication Number WO 98/53817, published Dec. 3, 1998 (the disclosure of which is incorporated herein by reference in its entirety) and references cited therein describe disorders mediated by xcex14xcex27. This reference also describes an assay for determining antagonism of xcex14xcex27 dependent binding to VCAM-Ig fusion protein.
Additionally, compounds that bind xcex1dxcex22 and xcex1excex27 integrins are particularly useful for the treatment of asthma and related lung diseases. See, for example, M. H. Grayson et al., J. Exp. Med. 1998, 188(11) 2187-2191. Compounds that bind xcex1excex27 integrin are also useful for the treatment of systemic lupus erythematosus (see, for example, M. Pang et al., Arthritis Rheum. 1998, 41(8), 1456-1463); Crohn""s disease, ulcerative colitis and infammatory bowel disease (IBD) (see, for example, D. Elewaut et al., Scand J. Gastroenterol 1998, 33(7) 743-748); Sjogren""s syndrome (see, for example, U. Kroneld et al., Scand J. Gastroenterol 1998, 27(3), 215-218); and rheumatoid arthritis (see, for example, Scand J. Gastroenterol 1996, 44(3), 293-298). And compounds that bind xcex16xcex21 may be useful in preventing fertilization (see, for example, H. Chen et al., Chem. Biol. 1999, 6, 1-10).
The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. Unless otherwise stated, all temperatures are in degrees Celsius.